Special Focus on Cancer Research News
An eye on immunotherapeutics
A roundup of recent research efforts to advance immuno-oncology efforts
The field of oncology-focused immunotherapy seems to only keep growing as more and more potential immunotherapeutic agents emerge as candidates for treating various cancers—or perhaps even one day preventing them from taking hold in a person’s body at all.
And, appropriately enough for a growing field against a foe that grows uncontrollable, one can only hope that the growth of the science can one day outpace the speed of cancers’ spread.
One very recent piece of news in this area of research came at the end of January from Immunovaccine Inc., a clinical-stage immuno-oncology company that was announcing the publication of a preclinical study using magnetic resource imaging (MRI) to follow cancer peptide uptake in tumor models, and to correlate this immune activation to the resulting anticancer T cell activity.
The Journal of Biomedical Science study, titled “Unique Depot Formed by an Oil Based Vaccine Facilitates Active Antigen Uptake and Provides Effective Tumour Control,” compared the mechanism of action (MOA) of Immunovaccine’s platform for immunotherapeutic stimulation with other technologies. In the study, researchers concluded that Immunovaccine’s delivery technology had a fundamentally unique MOA. This MOA enabled active and prolonged immune stimulation, as well as better tumor control, as compared to other technologies examined in the study.
“These findings demonstrate why we’re able to generate sustained immune system activation, and also why measuring the level of immunogenicity at a single point in time is often not predictive of anti-cancer activity,” said Marianne Stanford, Immunovaccine's vice president of research and senior author of the study. “Our approach to generating immune responses did not follow the pattern described for classical vaccines, in which a peak primary immune response rapidly subsides and requires secondary stimulation for protection. Instead, T cell activation induced by our technology is correlated with both prolonged traffic to lymph nodes, and enhanced efficacy in preventing tumor progression.”
Unlike other technologies that rely on a slow release of antigens at the site of injection, Immunovaccine’s delivery formulation entraps the immuno-stimulating agents at the injection site. This ‘depot’ effect forces an active uptake by immune cells, rather than a passive diffusion at the injection site, according to the company; hence, the immune-stimulating components are protected from degradation, are delivered over a prolonged period of time to antigen-presenting cells, and are actively transported to the lymph nodes.
Meanwhile, around the same time, Bristol-Myers Squibb Co. announced new data from a cohort of the Phase 2 CheckMate-142 trial evaluating Opdivo (nivolumab) and Yervoy (ipilimumab) for the treatment of patients with DNA mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC)—continuing research into the promising area of of PD-1-plus-CTLA4 combo therapy.
With a median of 13.4 months of follow-up, the primary endpoint of objective response rate per investigator assessment was 55 percent, and responses were durable, with median duration of response not yet reached and 94 percent of responses ongoing at time of data cutoff. The overall survival rate at one year was 85 percent.
“These results demonstrate that Opdivo plus Yervoy provides durable clinical benefit in patients with dMMR or MSI-H metastatic colorectal cancer,” said Dr. Thierry André, head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris. “The combination of Opdivo and Yervoy may represent an important advance for these distinct biomarker-defined patients, who historically have poorer outcomes compared to metastatic colorectal cancer patients whose tumors are mismatch repair proficient or microsatellite stable.”
“The Opdivo and Yervoy combination has demonstrated efficacy across tumors in a broad range of patients, and we are very encouraged to see that the complementary effect of this combination has the potential to increase antitumor activity in patients with dMMR or MSI-H metastatic colorectal cancer,” added Dr. Ian M. Waxman, development lead for gastrointestinal cancers at Bristol-Myers Squibb. “We are continuing to increase our understanding of the benefit of immuno-oncology-based combinations and look forward to further evaluating the potential of our immunotherapy treatments in colorectal cancer patients.”
Also in January, Bavarian Nordic A/S announced the initiation of a clinical trial of BN-Brachyury, a novel cancer immunotherapy candidate designed to target brachyury, a key driver of cancer metastasis in several tumor types. The open-label Phase 1 trial will evaluate the safety and tolerability of the MVA-BN Brachyury vaccine, followed by a brachyury-encoded fowlpox (FPV) booster in patients.
The trial will enroll up to 10 patients with metastatic or unresectable locally advanced malignant solid tumors. Patients will receive two prime doses of MVA-BN Brachyury, followed by multiple booster doses with FPV-Brachyury. The primary endpoint of the study is safety and tolerability, and secondary endpoints include immunologic responses as measured by an increase in brachyury-specific T cells and other tumor-associated antigens, as well as evidence of clinical benefit such as progression-free survival and objective response.
“The brachyury target represents an exciting new approach to attacking multiple cancers and deadly metastasis,” commented Paul Chaplin, president and CEO of Bavarian Nordic. “Based on clinical results to date, we believe that BN-Brachyury may be a viable treatment option for patients with various forms of cancer. We look forward to further expanding the program with a Phase 2 study later this year in patients with chordoma—a rare tumor of the spine known to overexpress brachyury, for which there are currently no systemic treatments of proven efficacy available.”
Also on the clinical trial front, Genentech, a member of the Roche Group, recently announced results from the Phase 3 IMpower150 study of Tecentriq (atezolizumab) and Avastin (bevacizumab) plus chemotherapy (carboplatin and paclitaxel) in people with previously untreated, advanced non-squamous non-small cell lung cancer (NSCLC). The study showed that people who received Tecentriq and Avastin plus chemotherapy had a 38-percent reduced risk of their disease worsening or death compared with those who received Avastin plus chemotherapy. Importantly, a doubling of the 12-month landmark progression-free survival rate was observed with the combination of Tecentriq and Avastin plus chemotherapy (37 percent) compared to Avastin plus chemotherapy (18 percent). The rate of tumor shrinkage, a secondary endpoint in the study, was higher in people treated with Tecentriq and Avastin plus chemotherapy compared with Avastin plus chemotherapy (64 percent vs. 48 percent).
“This Tecentriq study is the first positive Phase 3 combination trial that showed a cancer immunotherapy reduced the risk of the disease getting worse when used as an initial treatment in a broad group of people with advanced non-squamous NSCLC,” said Dr. Sandra Horning, chief medical officer and head of global product development for Genetech. “The IMpower150 study represents an important advance in lung cancer treatment, and we will submit these results to regulatory authorities around the world to potentially bring a new standard of care to people living with this disease as soon as possible.”
Finally, moving away from clinical trial news and back into the earlier-stage immune-oncology realm we started this article with, early January brought word from GeoVax Labs Inc., a biotechnology company developing human vaccines, that it is collaborating with Vaxeal Holding SA on the expansion of GeoVax’s cancer immunotherapy program.
GeoVax’s immuno-oncology program is based on its modified vaccinia ankara (MVA) virus-like particle (VLP) platform, which generates noninfectious VLPs in the individual being vaccinated. Gene sequences of target antigens are inserted into the MVA genome which drives their expression in infected cells. In addition, GeoVax introduces into the viral genome matrix sequences that incorporate antigens into VLPs and simultaneously facilitate their budding from the membranes of infected cells. In this way, vaccination induces two pools of antigens as targets for the immune response – virus-infected cells and released VLPs. This strategy mimics a natural viral infection, triggering the body to produce a robust and durable immune response with involvement of both antibodies and T cells.
With many advanced types of cancer, certain tumor-associated antigens such as CEA (cancer embryonic antigen), PSA (prostate specific antigen) and MUC1 (cell surface associated mucin 1) are overexpressed and aberrantly expressed. These antigens are often recognized as abnormal by patients’ immune systems but are not sufficiently immunogenic to trigger an effective immune response against the tumor. The tumor antigens must be presented to the body in a different form, or in a different way, to enlist the patient’s own immune system in fighting the cancer. GeoVax believes that its MVA-VLP platform may be able to do exactly this: train a patient’s own immune system to selectively seek and destroy the cancer cells bearing such antigens.
The collaboration between GeoVax and Vaxeal will include the design, construction, characterization and animal testing of vaccine candidates using GeoVax’s MVA-VLP vaccine platform. Vaccine antigens will include Vaxeal’s proprietary designed sequences.
TSRI researchers discover promising new anticancer strategy
LA JOLLA, Calif.—Scientists at The Scripps Research Institute (TSRI) say that they have discovered a compound that in laboratory tests irreversibly stops the growth of certain aggressive, treatment-resistant tumor cells—a compound that could be the first of a new class of anticancer drugs.
In their study, published in the Proceedings of the National Academy of Sciences under the title “A vimentin-binding small molecule leads to mitotic disruption in mesenchymal cancers,” the TSRI researchers showed that the new compound, FiVe1, blocks the growth of tumor cells that have undergone what researchers call the epithelial-mesenchymal transition (EMT), a process common in breast, colon, lung and other epithelial cell-derived tumors—known as carcinomas.
FiVe1 also blocks the growth of tumors called sarcomas, which originate from mesenchymal tissues including bone, fat, cartilage, muscle and blood vessels. The compound blocks cell division (mitosis) by binding to a structural protein, vimentin, that is produced abundantly in mesenchymal-type cells. Drugs that work via this mechanism should spare many of the healthy, fast-dividing cells, such as hair follicle cells, that are harmed by standard chemotherapy drugs.
“We hope that this discovery is going to lead to the development of effective therapies against a broad range of aggressive cancers,” said principal investigator Dr. Luke Lairson, an assistant professor of chemistry at TSRI.
Mesenchymal cells are one of the major cell types in developing embryos, and ultimately give rise to bone, muscle, fat, and certain other tissues. The EMT occurs naturally in early development to turn some epithelial cells—another broad cell type—into more free-ranging mesenchymal cells. The EMT also can be triggered by inflammation in adult tissues to transform epithelial cells into stem-like mesenchymal cells that aid wound healing.
The vast majority of cancer deaths are ultimately caused by recurrence following therapy or metastases. In previous studies, scientists had demonstrated that the EMT process enables carcinoma cells to adopt the properties of cancer stem cells, namely chemotherapy resistance and the ability to migrate in the body to form metastases.
The compound, in addition to blocking mitosis, caused EMT-transformed breast cancer cells to quickly revert to a lower-grade, epithelial appearance. Lairson and colleagues named the compound FOXC2-inhibiting Vimentin effector 1 (FiVe1).
“Traditional anti-mitosis drugs target proteins such as microtubules that are basic features of the cell division apparatus,” said lead author Dr. Michael J. Bollong, a Scripps Fellow in the Department of Chemistry. “We’ve shown for the first time here that targeting an intermediate filament protein such as vimentin can also induce ‘mitotic catastrophe.’”
Further lab-dish tests showed that FiVe1 irreversibly blocks mitosis in several other EMT-transformed cancer cell lines, as well as in tumor cells originating from muscle, fat, cartilage and other mesenchymal tissues.
FiVe1’s selectivity for vimentin-containing mesenchymal cancer cells means that it wouldn’t have the same side-effects as traditional chemotherapy drugs. Vimentin is not expressed at significant levels in the hair follicle cells and mouth- and gut-lining epithelial cells damaged by standard chemotherapy drugs. “A drug that blocks mitosis by targeting vimentin should be less toxic than traditional chemotherapeutic drugs that target cell division,” Lairson said.
Standing tall in canine cancer research at JAX
FARMINGTON, Conn.—The Jackson Laboratory (JAX) recently unveiled the Tallwood Canine Cancer Research Initiative (TCCRI), which will create a biobank of dog tumors that the nonprofit biomedical research institution plans to use and share with researchers around the world to provide new insights into cures for cancer in humans and dogs.
As part of this initiative, JAX will identify and work closely with veterinary centers of excellence. When a canine patient at one of the JAX’s veterinary partner organizations is diagnosed with a cancer of interest, its owner can opt to have the veterinarian donate their dog’s tumor to TCCRI when it’s removed during the dog’s cancer treatment. JAX will use the tumor to create a patient-derived xenograft (PDX) cancer model and sequence each tumor model established, much like the organization’s human PDX resource. JAX will use these PDX models for its ongoing cancer research programs, as well as make them available to researchers around the world to accelerate the process of cancer treatment discovery.
“As a geneticist, when you learn that certain purebred dogs recurrently get the same cancer type and thus are predisposed to those cancers—despite differences in their environments—you reason that there’s probably something underlying in their genome that encourages that specific cancer type to form,” said Dr. Charles Lee, scientific director and professor at JAX Genomic Medicine. “By studying specific dog breeds’ genomes, we can work to identify which parts of the genome differ between breeds and could contribute to cancer. Subsequently, identifying corresponding regions in human genomes might potentially uncover new regulatory elements that encourage these types of cancers in humans. This strategy is particularly useful for cancers that are rare among humans, but commonly found in certain dog breeds.”
Canine cancers and human cancers have been shown to be quite similar. For example, dogs get the same kinds of brain cancers as people, and their immune systems react similarly to treatments.
“It’s remarkable how similar our species are in this area. I am optimistic we will discover important information about how to best treat man and man’s best friend,” Lee said.
Cancer Research UK scientists halt breast cancer spread
LONDON—According to scientists at Cancer Research UK, an amino acid called asparagine is essential for the spread of breast cancer, and restricting that amino acid prevented cancer cells from metastasizing to other parts of the body in mice.
As Cancer Research UK notes, most breast cancer patients do not die from their primary tumor, but rather from the spread of cancer to the lungs, brain, bones or other organs. To be able to spread, cancer cells first need to leave the original tumor, survive in the blood as circulating tumor cells and then infiltrate other organs.
The researchers found that blocking the production of asparagine with a drug called L-asparaginase in mice, and putting them on a low-asparagine diet, greatly reduced the breast cancer’s ability to spread.
In the future, the scientists believe that alongside conventional treatments like chemotherapy, breast cancer patients could be given a diet in hospitals that restricts asparagine to help stop the disease spreading and improve outcomes. Their findings also suggest this could have implications for other cancer types, including kidney and head and neck cancers.
“Our work has pinpointed one of the key mechanisms that promotes the ability of breast cancer cells to spread,” said Prof. Greg Hannon, lead author of the study. “When the availability of asparagine was reduced, we saw little impact on the primary tumor in the breast, but tumor cells had reduced capacity for metastases in other parts of the body.”
Biothera evaluates combo of Imprime PGG and pembrolizumab
EAGAN, Minn.—Biothera Pharmaceuticals Inc. in February announced that patient treatment has commenced in its Phase 2 clinical study in squamous cell carcinoma of the head and neck (SCCHN). The research collaboration with Merck & Co. (known as MSD outside the United States and Canada) will evaluate Biothera’s Imprime PGG in combination with Keytruda (pembrolizumab), Merck’s anti-PD-1 therapy, in second- and third-line patients with SCCHN.
The study will test the potential of combining an innate immune modulator with a targeted adaptive immune system therapy to shrink tumors; this study is the second clinical research collaboration with Merck for Biothera.
Imprime PGG is an investigational PAMP (pathogen associated molecular pattern) that activates a cascade of innate immune system responses that culminate in T cell activation and cancer cell killing. Keytruda is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Preclinical studies show the therapeutic synergy of combining Imprime PGG and immune checkpoint inhibitor antibodies.